KR20080043811A - Method of obtaining 3,3-diphenylpropylamines - Google Patents

Abstract

The invention relates to a method of obtaining 3,3-diphenylpropylamines (I), wherein R1 is H, alkyl, haloalkyl or alkoxyalkyl, R2 is alkyl, alkoxy, halogen, NO2, CN, CHO, which may be free or protected, CH2OH or COOR6, and R3 and R4 are selected independently from H and alkyl or together form a ring with between 3 and 7 members with nitrogen to which they are bound. The inventive method consists in reacting a propylenephenylamine and a disubstituted aromatic hydrocarbon and, if necessary, separating the desired enantiomer or the mixture of enantiomers, and/or converting the compound (I) into a salt. Compounds (I) are muscarinic receptor antagonists which can be used in the treatment of urinary incontinence and other symptoms of urinary bladder hyperactivity. Said compounds include tolterodine.

Description

Method for obtaining 3,3-diphenylpropylamine {METHOD OF OBTAINING 3,3-DIPHENYLPROPYLAMINES}

The present invention relates to a process for obtaining these salts comprising 3,3-diphenylpropylamine, their enantiomers or mixtures thereof or pharmaceutically acceptable salts.

3,3-diphenylpropylamine acts as muscarinic receptor antagonists and is known to be effective in the treatment of toll room and bladder hyperactivity symptoms. Examples of the compound include compound N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine, and the (R) enantiomer thereof is tolterodine. , Compound (R)-(+)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine [(R) -tolerodine]. International patent application WO 98/03067 discloses (S) enantiomers, (S)-(-)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-propylamine or (S) -Tolterodine and their use to treat urinary and gastrointestinal disorders are described. US 6,538,035 describes the use of tolterodine and some derivatives thereof for treating asthma in mammals.

Patent US 5,382,600 describes tolterodine and other 3,3-diphenylpropylamine analogs. The patent generally describes several methods for preparing tolterodine and the like based on the substitution of tosylate with diisopropylamine. The method has several disadvantages. This substitution reaction occurs very slowly and therefore takes several days to carry out the reaction and the overall yield is also low. Some reactants used such as methyl iodide and lithium aluminum hydride are expensive and their use is accompanied by toxicity. All of them are expensive in the whole way and low in productivity.

US Pat. No. 5,922,914 describes another method for obtaining tolterodine. The method is carried out by reducing 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one from toluene with diisobutylaluminium hydride (DIBAL), followed by amination and reduction. Obtaining the corresponding hemiketal 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol to afford semi tolterodine. This method also has some drawbacks because expensive and toxic DIBAL reactants are used and therefore are not suitable for industrial implementation.

International patent application WO 03/014060 solves some of the problems of the previous method, but still yields several problematic steps, in particular intermediate 3- (2-methoxy-5-methylphenyl) -3-phenylpropanol. This step describes a method for obtaining tolterodine, which comprises converting tosylate derivatives, and subsequently replacing the tosylate with diisopropylamine. These steps still have serious problems, for example having steric hinderance in diisopropylamine in the tosylate substitution reaction, making nucleophilic substitution reactions difficult, requiring high temperatures for this, In addition, the reaction time they contain is long, it takes several days.

Another approach to preparing (R) -tolerodine enantiomers is described in US Pat. No. 6,310,248 or in J. Org. Formed by several mirror image synthesis as described in Chem 1998, 63, 8067-8070, it is generally described how it is necessary to use expensive reactants, respectively, asymmetric inducers or chiral auxiliaries.

Another method for tolterodine synthesis that reduces costs for the process and at the same time achieves good yields and low toxicity applications is described in Spanish patent application ES 2,235,648. This statement describes obtaining tolterodine by means of a synthetic route comprising a reduction amination reaction between a 3,3-diphenylpropanol derivative and diisopropylamine in the presence of a reducing agent. Nevertheless, obtaining starting aldehydes requires several synthetic steps, which drastically reduce the overall method.

Accordingly, there is a need to address the problems associated with the methods of the prior art and to use a more effective reactant in terms of cost and to further reduce the number of steps in the synthetic route leading to its yield. There is a need to provide a process for obtaining tolterodine and other 3,3-diphenylpropylamine analogs that improves the cost effective process by use. The method is preferably industrial

It must be applicable at the level and must be able to provide the intended product with good yield and quality.

The present invention provides another method for obtaining 3,3-diphenylpropylamine and in particular tolterodine, which overcomes the same problems as the ones described above in the synthesis art.

The solution proposed by the present invention is that the inventor of the present invention is a 3,3-diphenylpropylamine of the general formula (I) (defined below), an enantiomer thereof or a mixture thereof, a solvent compound thereof or In obtaining hydrates or salts thereof (including pharmaceutically acceptable salts and pharmaceutically unacceptable salts), propylenephenylamine and general formula (III) ( It has been observed that it is possible to produce these compounds with very good yields by reacting a di-substituted aromatic hydrocarbon (as defined below) with a Friedel-Crafts type aromatic nucleophilic substitution reaction means. That is based on the fact. The compounds of formula (II) are commercially available and can be obtained from cost effective starting materials.

The method as provided by the present invention has the advantage that the number of synthetic steps is significantly reduced compared to the methods of the prior art and at the same time performed in simple steps but with a very high yield. The method is also non-toxic, starting from low cost non-toxic reactants, 3,3-diphenylamine, and in particular N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3 To provide phenylpropryl-amines, enantiomers or mixtures thereof, solvates, hydrates or salts thereof, in particular pharmaceutically acceptable salts thereof, in pharmaceutically good quality in good yields. . All of these help to reduce the overall cost of implementing the method, which is economically beneficial and allows it to be implemented at an industrial level.

Accordingly, according to one example, the present invention relates to a method for obtaining 3,3-diphenylpropylamine of general formula (I), which is a compound of general formula (II) of propylenephenylamine and general formula (III). Reaction of the disubstituted aromatic hydrocarbons, and, if desired, isolating the intended (R) or (S) enantiomer or mixture of enantiomers, and / or the compounds of formula (I) Converting to a salt.

Compounds of formula (II) useful for the synthesis of compounds of formula (I) can be readily obtained from commercially available low cost starting compounds. Accordingly, according to another embodiment, the present invention is directed to a nucleophilic substitution reaction means between a compound of formula (IV) (defined below) and a first or second amine of formula (V) (defined below). A method for obtaining 3,3-diphenylamine of formula (I) from a compound of formula (II) obtained by a process comprising a reaction step.

The method for obtaining the compound of formula (II) is one of the other objects of the present invention.

In another example, the invention relates to acid addition salts of compounds of formula (II).

In one embodiment of the present invention, the present invention provides a process for obtaining 3,3-diphenylpropylamine, general formula (I), or mixture thereof, solvent compound, hydrate, or salt thereof of general formula (I) As for 1);

here,

R ₁ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or an alkoxyalkyl of the formula — (CH ₂ ) nOR ₅ wherein n is an integer of 1 to 3 and R ₅ is C ₁ -C ₆ alkyl And;

R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO _2, CN, free or protected CHO, CH ₂ OH or R ₆ is H or C ₁ -C ₆ alkyl group, a COOR ₆ ;

R ₃ and R ₄ are independently selected from H and C ₁ -C ₈ alkyl or they are selected together with nitrogen formed by bonding a ring having 3 to 7 components;

The method,

a) R ₃ and R ₄ are as described above

A compound of formula (II),

R ₁ and R ₃ are as described above

A reaction step of; And

b) if necessary, separating (R) or (S) enantiomers, or mixtures of enantiomers, and / or converting the compounds of general formula (I) to their salts.

As used herein, the term "haloalkyl" relates to a straight or branched chain alkyl group substituted with one or more halogens such as fluorine, chlorine, bromine or iodine.

The term “protecting CHO” relates to a carbonyl group that is functionalized or protected by a group that is typically used to cause other functional groups of the compound to react while blocking the function of the carbonyl group. The group can be optionally removed to unmask the carbonyl group. Suitable protecting groups for carboxyl groups are well known in the art and include those described by Green, TW, "Protective Groups in Organic Synthesis," John Willy & Sons, New York 1999. Examples of protecting groups for carboxyl groups include, among others, esters such as alkyl esters or methyl esters, ethyl esters, tert-butyl esters or benzyl esters, for example alkoxy groups such as dimethoxy, diethoxy Or other C ₁ -C ₆ -alkoxy, diphenoxy, cyclic ketals such as dioxane, 1,3-dioxane or catechols.

The product of formula (II) may be obtained by the process described in the prior art or by the other process provided by the present invention which will be described in detail below. Compounds of formula (III) are known and commercially available.

The reaction of propylenephenylamine of general formula (II) with a disubstituted aromatic hydrocarbon of general formula (III) is carried out by the Friedel-Krafts type of the ortho position of the aromatic ring present in the compound of general formula (III). It is a nucleophilic substitution reaction and is carried out in a reaction medium comprising an acid which serves as a catalyst for said Friedel-Krafts type aromatic nucleophilic substitution reaction. Substantially any type of acid can be used to carry out this reaction. This reaction generally results in high yields, which typically consist of 85% to 90%, contributing to increasing the overall yield of the process for obtaining compounds of formula (I) provided by the present invention.

In certain embodiments, the acid is an inorganic acid. Examples of the inorganic acid to be used include the following, and examples thereof include, but are not limited to, hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid, and the like and mixtures thereof. The inorganic acid can be used in the form of an aqueous suspension or solution.

In another specific embodiment, the acid is an organic acid, preferably a rigid organic acid. Illustrative examples of the organic acid used include the following, and include sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and the like, acetic acid, trifluoroacetic acid, and the like, or mixtures thereof. no.

In other specific embodiments, the reaction medium comprises one or more inorganic acids and one or more organic acids. Examples of the inorganic and organic acids used are as mentioned above, but are not limited thereto. In certain embodiments, the reaction medium comprises organic acids such as, for example, inorganic and acetic acids selected from the group consisting of hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid and mixtures thereof.

In other specific embodiments, the acid is a Lewis acid such as, for example, AlCl ₃ , SnCl ₄ , ZnCl ₄ , BF ₃ , or the like, or a mixture thereof.

The aromatic nucleophilic substitution reaction may be carried out under different conditions depending on the reactivity of the compound of general formula (III).

When R ₁ in the compound of formula (III) is hydrogen, the aromatic nucleophilic substitution reaction can be carried out in several ways, for example:

-1 to 4 equivalents of the derived phenol of the general formula (III) [R ₁ = H] relative to the equivalent of the compound of the general formula (II) are used as organic acids, for example aqueous hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid. Or a mixture thereof, optionally using a reaction medium comprising, for example, an organic acid such as acetic acid, at 60 ° C. to reflux temperature, preferably at 80 ° C. to reflux temperature;

Lewis acids are used, in which case the aromatic nucleophilic substitution reaction preferably takes from 1 to 4 equivalents of the derived phenol of formula (III) [R ₁ = H] relative to the equivalent of compound of formula (II). Used, in a reaction medium comprising organic solvents such as dichloromethane, 1,2-dichloroethane, acetic acid and the like, in addition to Lewis acids, from room temperature (typically 18 ° C. to 22 ° C.) to reflux temperature, preferably room temperature And at a temperature of 60 ° C., for example, as the Lewis acid, SnCl ₄ , ZnCl ₂ , BF _3, etc. may be used, and preferably AlCl ₃ may be used as the Lewis acid; or,

-1 to 4 equivalents of the derived phenol of the general formula (III) [R ₁ = H] to the equivalent of the general formula (II) compound, for example, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like, And optionally, for example, room temperature (typically from 18 ° C. to 22 ° C.) and reflux in a reaction medium consisting of high boiling point solvents such as toluene, xylene, and / or other (organic or inorganic) acids, acetic acid Temperature, preferably at 40 ° C. to reflux temperature.

When R ₁ is not hydrogen in the compound of formula (III), for example, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, or n and R ₅ are as defined above, ₂ ) When alkoxyalkyl of nOR ₅ , these aromatic nucleophilic substitution reactions can be carried out by other methods, for example;

4 to 16 equivalents of derived alkoxy of formula (III) (R ₁ ≠ H), relative to the equivalent of the compound of formula (II), to inorganic acids (except hydrobromic acid), for example, aqueous perchloric acid In a reaction medium consisting of sulfuric acid, hydrochloric acid, phosphoric acid or a mixture thereof, at 80 ° C. to reflux temperature, preferably at reflux temperature;

4 to 16 equivalents of alkoxy of general formula (III) (R ₁ ≠ H) relative to the equivalent of the compound of general formula (II), wherein the compound of general formula (II) also acts as solvent, For example, in a reaction medium consisting of AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF _3, etc., the method is used at a temperature of 20 ° C. to 100 ° C., preferably 40 ° C. to 60 ° C .; or

4 to 12 equivalents of alkoxy of formula (III) (R ₁ ≠ H) relative to the equivalent of the compound of formula (II) are selected from organic acids, for example p-toluenesulfonic acid, methanesulfonic acid, and the like, and As an organic acid such as acetic acid or the like at 80 ° C. to reflux temperature, preferably 100 ° C. to reflux temperature.

Compounds of general formula (I) have chiral carbons, and therefore are present in the form of isolated (R) or (S) enantiomers or in the form of mixtures of such enantiomers. As used in this description, the terms "mixture of enantiomers" or "enantiomeric mixtures" include mixtures enriched in racemic mixtures and any one of enantiomers. The obtained (R) and (S) enantiomers of the compounds of general formula (I) can be separated by conventional methods of decomposing the mixture of enantiomers, for example by fractional distillation, conventional chromatography methods. Can be. In certain embodiments, the compounds of formula (I) obtained by the process provided by the invention are obtained in the form of enantiomeric mixtures, for example in the form of racemic mixtures. Thus, if necessary, the obtained mixture of enantiomers is dissolved with the corresponding enantiomer to obtain the desired enantiomer. In certain embodiments, the enantiomer is enantiomer (R) [(+)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine], or Tolterodine, also known as (R) -tolerodine, is pharmaceutically useful. In another specific embodiment, the enantiomer is an enantiomer (S) [(-)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine] Or (S) -tolterodine, which is therapeutically applied.

The mixture of enantiomers is decomposed, for example, by using a chiral chromatography column or by fractional determination of the salts of the enantiomers corresponding to the (chiral) selective active acids. In certain embodiments, the (R) anthiomer of the compound of formula (I) is separated by optical resolution by treating the enantiomer with L-tartaric acid. (R) -tolterodine L-tartrate salt or any other salt that corresponds to a suitable chiral acid is required as many times as necessary to obtain (R) enantiomers of compounds of formula (I) having the desired purity. As much as it can be crystallized. In addition, if desired, the enantiomers obtained are prepared by salts, such as pharmaceutically acceptable salts or pharmaceutically unacceptable salts thereof, by methods commonly known to those skilled in the art. Can be switched.

The compound of formula (I) is an amine, which can form addition salts with organic or inorganic acids when reacted with a suitable acid. Such salts may include pharmaceutically acceptable salts and pharmaceutically unacceptable salts, which may sometimes be useful for the synthesis, separation or purification of general formula (I) or pharmaceutically desired salts. Salts of the above illustrated examples include, but are not limited to, hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate . The salts can be obtained by conventional methods by reacting the free amine with the corresponding acid. In certain embodiments, the salt is a pharmaceutically acceptable salt, for example hydrobromide or tartrate. The salts can be obtained by reaction of free amines with hydrobromic acid or by treatment with hydrobromic acid in the presence of acetic acid or with tartaric acid. If desired, the addition salt can be selectively converted to the corresponding free amine by conventional methods, for example by changing the pH of the solution consisting of the salt until a free amine is obtained.

Compounds of formula (I) may be obtained in free base or in salt form. In both cases, this can be obtained in crystalline form, as a free compound and a solvent compound (eg hydrate), both of which correspond to the invention. Solvation is generally known in the art.

Method [1] of the present invention provides a compound of formula (I), enantiomers, hydrates, solvent compounds, and salts thereof. In certain embodiments, the process is a compound of formula (I) wherein R ₁ is H or methyl, R ₂ is methyl and R ₃ and R ₄ are isopropyl, preferably R ₁ is H, and R ₂ is Compounds of formula (I) wherein methyl is and R ₃ and R ₄ are isopropyl, as well as enantiomers or mixtures thereof and salts thereof (pharmaceutically acceptable salts and pharmaceutically unacceptable salts) Inclusive). In certain embodiments, the methods provide the compound N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine, an enantiomer thereof or a salt thereof. In certain preferred embodiments, the method [1] of the present invention comprises compounds (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or Salts thereof, such as hydrobromide or tartrate.

In another embodiment, the invention relates to 3,3-diphenylpropylamine of the general formula (I ′). To an enantiomer or mixture thereof, solvate, hydrate or salt thereof,

here,

R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO ₂ , C _N , CHO, CH ₂ OH or COOR ₆ , which may be free or protected, wherein R ₆ is H or C _1- C ₆ alkyl;

R ₃ and R ₄ are selected together with H, C ₁ -C ₈ alkyl, or nitrogen formed by bonding a ring having 3 to 7 components;

This way,

a) R ₃ and R ₄ are as defined above

A compound of formula (II),

Alkoxyalkyl of the formula-(CH ₂ ) nOR ₅ , wherein R ' ₁ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or n is an integer from 1 to 3, and R ₅ is C ₁ -C ₆ alkyl ego ; And,

R ₂ is reacted with a compound of formula (III ′) as defined above;

R ' ₁ , R ₂ , R ₃ and R ₄ generate a compound of formula (I ″) as defined above;

b) converting R ' ₁ to hydrogen to obtain a compound of formula (I'); And

c) if desired, separating the intended (R) or (S) enantiomers, or mixtures of enantiomers, and / or converting the compounds of formula (I ′) to their salts. do.

The product of formula (II) can be obtained by the process described in the prior art or by the other methods provided by the invention described below. Compounds of general formula (III ′) are known and commercially available.

The reaction of propylphenylamine of general formula (II) with a disubstituted aromatic hydrocarbon of general formula (III ') is carried out by the Friedel-Crafts type of ortho position of the aromatic ring present in the compound of general formula (III'). It is an electrophilic substitution reaction and is carried out in a reaction medium consisting of an acid which acts as a catalyst for an aromatic electrophilic substitution reaction of the Friedel-Krafts type. Nevertheless, unlike the process of the invention [1], in this method this step cannot be carried out by using an aqueous hydrobromic acid capable of dialkylating the alkoxide group of the molecule and thus, other acids, eg For example, aqueous inorganic acids such as sulfuric acid, perchloric acid, and the like and mixtures thereof; Organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and the like, and mixtures thereof or Lewis acids such as AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF ₃ and the like are used.

In certain embodiments, the acid is an inorganic acid except hydrobromic acid for the reasons mentioned above. Examples of inorganic acids that can be used generally include, but are not limited to, aqueous perchloric acid, sulfuric acid, and the like, and mixtures thereof.

In another specific embodiment, the acid is an organic acid, preferably a rigid organic acid. Illustrative examples of organic acids that may be used include, but are not limited to, sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and the like, acetic acid, trifluoroacetic acid, and the like, or mixtures thereof.

In other specific embodiments, the reaction medium comprises one or more inorganic acids, except hydrobromic acid, and one or more acids. Exemplary embodiments of the inorganic and organic acids that can be used are as already mentioned above, but not limited thereto. In certain embodiments, the reaction medium consists of, for example, inorganic acids selected from the group consisting of perchloric acid, sulfuric acid, and mixtures thereof and organic acids such as acetic acid.

In another specific embodiment, the acid is a Lewis acid, for example AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF ₃ , or the like, or a mixture thereof.

The aromatic electrophilic substitution reaction may be carried out under different conditions depending on the reactivity of the compound of general formula (III ′). For example, the aromatic electrophilic substitution reaction may be performed as follows.

4 to 16 equivalents of the alkoxy of formula (III ′) to the equivalent of the compound of formula (II) generally consist of aqueous inorganic acids (except hydrobromic acid), for example sulfuric acid, perchloric acid, etc. In the reaction medium, at 80 ° C. to reflux temperature, preferably at reflux temperature; or

4 to 16 equivalents of the derived alkoxy of formula (III ′) to the equivalent of the compound of formula (II), which can act as a solvent, for example, a Lewis acid such as AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF _In a reaction medium consisting of _3, etc., at a temperature of 20 ° C to 100 ° C, preferably 40 ° C to 60 ° C; or

4 to 12 equivalents of the derived alkoxy of formula (III ′) to the equivalent of the compound of formula (II) are converted to organic acids such as p-toluenesulfonic acid, methanesulfonic acid, and the like and optionally In inorganic acids such as acetic acid, etc., at 80 ° C. to reflux temperature, preferably at 100 ° C. to reflux temperature.

Step d) capable of converting R ′ ₁ [C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or — (CH ₂ ) nOR ₅ alkoxyalkyl] to hydrogen may be carried out by any method known in the art. Is performed; This compound is carried out by subjecting the compound to a dialkylation reaction by treating with an organic acid such as aqueous hydrobromic acid, optionally acetic acid. In certain embodiments, the dialkylation reaction is carried out by treatment with a mixture of aqueous hydrobromic acid and acetic acid.

The compound of general formula (I ′) is chiral carbon and therefore exists in the form of its isolated (R) or (S) enantiomer or in the form of a mixture of said enantiomers. The obtained (R) or (S) enantiomer of the compound of the general formula (I ') can be dissolved in a conventional method capable of dissolving a mixture of enantiomers, for example, fractional distillation and conventional chromatographic methods. Can be separated by. In certain embodiments, the compounds of formula (I ′) obtained by the process provided by the invention are obtained in the form of racemic mixtures, for example in the form of a mixture of enantiomers. Thus, if necessary, the obtained mixture of enantiomers can be decomposed into its corresponding enantiomers to obtain the intended enantiomers. In certain embodiments, the enantiomer is (R) enantiomer [(R)-(+)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl Amine], or tolterodine, also known as (R) -tolerodine, and is pharmaceutically useful. In another specific embodiment, the enantiomer is (S) enantiomer [(S)-(-)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl Propylamine], or (S) -tolterodine, which also has therapeutic applicability.

The mixture of enantiomers can be decomposed by any conventional method, for example, by using a chiral chromatography column or by fractional determination of salts of the enantiomers corresponding to appropriate (chiral) optionally active acids. Can be. In certain embodiments, the (R) enantiomer of the compound of formula (I ′) is separated by optical resolution by treating the mixture of enantiomers with L-tartaric acid. (R) -tolterodine L-tartrate salts or any other salts corresponding to appropriate chiral acids may be used as needed until a (R) enantiomer of a compound of formula (I ') with the desired purity is obtained. It can be crystallized as many times. In addition, if desired, the enantiomer obtained can be converted to its pharmaceutically acceptable salts by conventional methods known by those skilled in the art.

The compound of formula (I ') is an amine and can form addition salts with organic or inorganic acids when it is reacted with a suitable acid. Such salts include pharmaceutically acceptable salts and pharmaceutically unacceptable salts, which may optionally include the synthesis, isolation, or of the intended compound of formula (I ′) or a pharmaceutically acceptable salt, or It may be useful for purification. Illustrative examples of such salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate It is not. The salts can be obtained by conventional methods by reacting the free amine with the acid in question. In certain embodiments, the salt is, for example, a pharmaceutically acceptable salt, hydrobromide or tartrate. The salts can be obtained according to the reaction of free amine with hydrobromic acid or by addition reaction by treatment with hydrobromic acid in the presence of acetic acid or by reaction with tartaric acid. If desired, the addition salt can be converted to the corresponding free amine in a conventional manner, for example by varying the pH of the solution consisting of the salt until a free amine is obtained.

Compounds of formula (I ′) may be obtained in free base or in salt form. In both cases it can be obtained as free compound and solvate (eg hydrate), both of which are included in the scope of the invention. Solvation methods are generally known in the art.

This process provides compounds of formula (I '), enantiomers, hydrates, solvates and salts thereof. In certain embodiments, the process comprises a compound of formula (I ′) wherein R ₂ is methyl and R ₃ and R ₄ are both isopropyl, as well as enantiomers or mixtures thereof and salts thereof. (Including pharmaceutically acceptable salts and pharmaceutically unacceptable salts). In certain embodiments, the methods provide the compound N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine, an enantiomer thereof or a salt thereof. In certain embodiments, the method comprises compounds (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or salts thereof, such as hydro Bromide or tertrate is provided.

Compounds of formula (II), starting products of the process of the invention or compounds of formula (I ′) may be obtained by a process comprising the step of reacting with a first or second amine of formula (V). Can be.

Where Y is the exit group,

Wherein R ₃ and R ₄ are independently selected with hydrogen and the nitrogen formed by bonding straight or branched C ₁ -C ₈ alkyl or a ring in which they have 3 to 7 components.

This method involves the nucleophilic substitution of the leaving group Y with an amine of the general formula (V) in a proportion varying from 1 to 8 equivalents, preferably from 2 to 6 equivalents relative to the equivalent of the compound of the general formula (IV) Steps. Compounds of general formula (IV) having a certain leaving group, preferably some good leaving group, can be used, although Y is halogen, tosylite or mesylate, Y is preferably Br or Cl, and cost For efficient reasons, it is preferable that Y is Cl. This reaction is carried out in a solvent. Alcohols, toluene, xylene, acetonitrile, acetone, dimethylformamide (DMF), 1,2-dichloroethane, and the like, preferably alcohols, toluene or xylene, more preferably alcohols having 5 or less carbon atoms For example, ethanol or isopropanol, preferably ethanol can be used as the solvent. This reaction is carried out at room temperature (typically from 18 ° C. to 22 ° C.) to reflux temperature, preferably from 30 ° C. to 78 ° C., more preferably from 40 ° C. to 70 ° C.

In certain cases using alcoholic solvents such as ethanol or isopropanol, the reaction is carried out at temperatures consisting of 0 ° C. to the boiling point of the solvent. In turn, when toluene or xylene is used as the solvent, the reaction is carried out at a temperature consisting of 80 ° C. to the boiling point temperature of the solvent.

In the art, as a leaving group (Msuyama, Y, et al., Chemistry Lett., 1995, 12, 1120), a starting reactant such as a compound of formula (IV) containing an OH group Obtaining a compound included in (II); Nevertheless, in the presence of SnCl ₂ , the action of a catalyst such as Pd (PPh ₃ ) ₄ needs to prevent the amine from reacting with the double bond. Contrary to expectations, in the process for obtaining the general formula (II) provided by the present invention, the first or second amine of the general formula (V) does not attack the double bond of the propene moiety and the double bond Leaving group Y is substituted without the required compound to deactivate.

In certain embodiments, this method allows to obtain a compound of formula II wherein R ₃ and R ₄ are isopropyl.

The compound of formula (II) is an amine and can form addition salts with organic and inorganic salts when it is reacted with a suitable acid. Illustrative examples of such salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate. The salts can be obtained by conventional methods by reacting the free amine with the acid in question. If desired, the addition salt can be selectively converted by conventional methods, for example by varying the pH of the solution comprising the salt until a free amine is obtained.

Acid addition salts of formula (II) are themselves further examples of the invention. Accordingly, in another embodiment, the present invention relates to acid addition salts of compounds of formula (II) consisting of the compounds of formula (II) and acids. The acid can be an organic or inorganic acid. It is not intended to limit the exemplification, and the anion of the acid may be hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate and the like. . In other specific embodiments, R ₃ and R ₄ are both isopropyl. In another specific embodiment, the salt is a hydrochloride or hydrobromide of a compound of formula (II), preferably N, N-diisopropyl-3-phenyl-2-propenamine hydrochloride or N, N-diisopropyl-3-phenyl-2-propeneamine hydrobromide.

In another embodiment, the present invention provides a process of the present invention for obtaining 3,3-diphenylpropylamine of formula (I), enantiomers or mixtures thereof, solvates, hydrates, or salts thereof [2]. As to;

here,

R ₁ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or alkoxyalkyl of the formula — (CH ₂ ) nOR ₅ wherein n is an integer from 1 to 3 and R ₅ is C ₁ -C ₆ alkyl ;

R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO ₂ , CN, COOR wherein CHO, CH ₂ OH, R ₆ is free or protected, H or C ₁ -C ₆ alkyl group ₆ ;

R ₃ and R ₄ are independently selected from H and C ₁ -C ₈ alkyl or are selected together with nitrogen which is formed by bonding a ring having 3 to 7 components;

The method,

a) Y is an exit group

(IV)

A compound of formula (IV),

R ₃ and R ₄ are independently selected from hydrogen and straight or branched C ₁ -C ₈ alkyl, or independently selected with nitrogen formed by combining a ring having 3 to 7 components of formula (V) The first or second amine reacts;

Obtaining a compound of formula (II);

b) R ₁ and R ₂ reacting said compound of formula (III) with said compound of formula (II) as described above; And,

c) if desired, separating the desired (R) or (S) enantiomer, or a mixture of enantiomers, and / or converting a compound of formula (I) to a salt thereof do.

Step a) of the process [2] of the present invention corresponds to the steps described above in connection with the method of obtaining general formula (II), and steps b) and c) of the method of the method [1] of the present invention. Corresponding to steps a) and b) and as described above.

Compounds of formula (I), as well as enantiomers or mixtures thereof, solvates, hydrates, or salts thereof, which can be obtained by the process [2] of the present invention, are considered to be reproducible in their contents. Corresponding to that described above in connection with the method [1] of the present invention.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention.

Example  One

N, N'- Diisopropyl -3- Phenyl -2- Propeneamine [ R ₃  And R ₄ Is a compound of formula (II) wherein isopropyl]

A) from cinnamil bromide

At one hour intervals, a solution of 10 g of cinnamil bromide (0.05 mol, 1 equiv) in 10 ml ethanol was added to a solution of 28.5 ml diisopropylamine (0.2 mol, 4 equiv) in 30 ml ethanol heated at 30 ° C. Add. After about 1 hour, the reaction was terminated and the solvent and the remaining diisopropylamine were distilled off under reduced pressure. 100 ml of toluene and 150 ml of water are mixed with the residue, the concentrated HCl is added until the pH is 1-2, and the phases are separated; The aqueous phase was basified by addition of sodium hydroxide until the pH was between 10 and 11, 150 ml of heptane was extracted and washed with water. The organic extract was distilled off under reduced pressure to yield 8.6 g (90% yield) oil by weight of the title product.

13 C-NMR (CDCl ₃ , δ in ppm): 137.82 (C), 132.12 (CH), 130.17 (CH), 128.71 (CH), 126.37 (CH), 48.46 (CH), 47.90 (CH ₂ ), and 20.98 (CH ₃ )

B) from cinnamil chloride

73 ml of cinnamil chloride solution (0.52 mol, 1 equivalent) in 80 ml of ethanol was added to a solution of 185 ml of diisopropylamine (1.30 mol, 2.5 equivalents) in 240 ml of ethanol heated at 50 ° C. at 1 hour intervals. . The reaction was held and terminated at 50 ° C. for 7 hours at 60 ° C. for 14 hours, and the solvent and the remaining diisopropylamine were distilled off under reduced pressure. 160 ml of toluene and 240 ml of water are mixed into the residue, concentrated HCl is added until pH is 1-2, the phases are separated and the aqueous phase is added sodium hydroxide until pH is 12-13 The mixture was extracted with 250 ml of heptane and washed with water. The organic extract was distilled off under reduced pressure to yield an oil having a weight of 76.71 g (67% yield) corresponding to the title product.

The product can be dissolved in ethanol and a solution of ClH (g) in ethanol can be added and precipitated as a white solid to separate as hydrochloride.

Example  2

N, N- Diisopropyl -3- (2- Hydroxy -5- Methylphenyl ) -3- Phenylpropylamine  purchase[ R _One this Hydrogen, R ₂ end Methyl , R ₃  And R ₄ Is a compound of formula (I) wherein isopropyl]

A) using aqueous hydrobromic acid (aq BrH) / acetic acid (AcOH)

5 g of N, N-diisopropyl-3-phenyl-2-propeneamine (0.023 mol, 1 equiv) and 6 g p-cresol (0.055 mol, 2.4 equiv) were mixed into a solution of 13 ml acetic acid. 15 ml of 48% HBr in water was added to the formed solution, which was heated to reflux temperature. At the end of the reaction, it was cooled and the solid formed was filtered and washed with water. The solid obtained forms N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine (tolerodine) in the form of crude hydrobromide, which is ethanol, methanol or isopropanol Can be recrystallized to yield purified N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine hydrobromide.

Yield of crude N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine: 6.56 g.

Yield of purified N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine: 4.8 g.

The reaction can be carried out alternately by heating at 100-110 ° C. with 70% HClO ₄ in water or aqueous sulfuric acid solution.

B) using p-toluenesulfonic acid TsOH / acetic acid (AcOH)

5 g of N, N-diisopropyl-3-phenyl-2-propeneamine (0.023 mol, 1 equiv) and 12 g p-cresol (0.055 mol, 4.8 equiv) were mixed into a solution of acetic acid. 21.86 g of p-toluenesulfonic acid was added over 30 minutes and the solution was heated at 50 ° C. over 8 hours and finally heated at 100 ° C. until the reaction was over. The volatiles were distilled off under reduced pressure and the reaction mixture was dispersed between 100 m of water and 100 ml of toluene, the pH of the formed suspension was maintained at 9-10, and the organic phase was separated. The solvent was purified by column chromatography on the reaction mass obtained by distillation under reduced pressure to give the title product in the form of an oil. 2 g of purified N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine base.

Example  3

N, N- Diisopropyl -3- (2- Methoxy -5- Methylphenyl ) -3-phenylpropylamine [ R _One  And R ₂ end Me Til R ₃  And R ₄ Is a compound of formula (I) wherein isopropyl]

A) using AlCl ₃

8 ml of anisole (0.065 mol, 8.2 equiv) and 2 g of N, N-diisopropyl-3-phenyl-2-propeneamine hydrochloride were placed in a 50 ml flask. 2.1 g AlCl ₃ (0.0157 moles, 2 equiv) was added to the cooled reaction mixture without exothermic treatment, while the temperature did not exceed 40 ° C. The suspension obtained was heated to 40 ° C. and maintained in this way for 15-30 hours, until the reaction was considered complete. Most present N, N-diiso with N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine as main impurity by high performance liquid chromatography (HPLC) Propyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine was observed. The reaction mixture was treated by adding 60 ml of water and extracting with 100 ml of dichloromethane. A further 100 ml of water was added to the organic extract and neutralized to pH 9-10, the phases were separated and an organic phase was obtained. The solvent was removed under reduced pressure and the resulting residue consisting of excess anisole and the title product was passed through a chromatography column and the title product was separated as an oil.

B) using sulfuric acid

46.8 ml of anisole (0.367 moles, 4 equiv) and 18 ml of water were added to the round bottom flask. The suspension obtained was cooled in an ice / water bath, held for approximately 30 minutes with 24.8 ml of 98% sulfuric acid, and maintained at a temperature below 40 ° C. The reaction mixture was heated to 100 ° C. and at this temperature 20 g of N, N-diisopropyl-3-phenyl-2-propenamine were added in base form to maintain at least 30 minutes. The reaction was monitored by HPLC for approximately 1-4 hours until it was finished. When this is terminated, 150 ml of water and 150 ml of toluene are added to leave the product in the aqueous phase and the anisole in the organic phase. Separation The anisole-free aqueous phase was neutralized until pH was 12-13 and separated with 150 ml heptane. The organic phase was distilled off under reduced pressure, changed to ethyl acetate and BrH in acetic acid was added dropwise to the solution to give N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenyl Propylamine precipitated in the form of hydrobromide, which was filtered and washed with more ethyl acetate. The mother liquor was neutralized and passed through a chromatography column to obtain a second fraction of the title product in the form of an oil. Approximate yield: 50%

C) use of perchloric acid

11.7 ml of anisole (0.092 mol, 4 equiv) and 1.5 ml of water are placed in a round bottom flask. 9.9 ml of 70% perchloric acid is added dropwise to this mixture, cooled in an ice bath and held for about 30 minutes. The reaction mixture is heated at 80 ° C. and the addition of 5 g of N, N-diisopropyl-3-phenyl-2-propeneamine is started and held for about 30 minutes. This reaction was followed by HPLC at one hour intervals; After 5-6 hours, the peak corresponding to the title product was observed as the main peak. (More than 80% purity when excess anisole is removed)

Example  4

(R)-(+)-N, N- Diisopropyl -3- (2- Methoxy -5- Methylphenyl ) -3- Phenylpropylamine  Tartrate [ R _One  And R ₂ end Methyl  And R ₃  And R ₄ Is a compound of formula (I) wherein isopropyl]

5.2 ml of NaOH (50%) was added N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine hydrobromide (53 g) in 750 ml CH ₂ Cl ₂ and 375 ml water. , 0.131 mole), and the pH was adjusted to 9.5 with acetic acid as needed. When this pH was reached, it was stirred for 45 minutes, which was extracted with CH ₂ Cl ₂ to give 42.55 g of free amine. Then, 29.43 g of L-tartaric acid solution dissolved in 280 ml of ethanol at 60 ° C. was added to the amine dissolved in 140 ml of ethanol at 60 ° C. The reaction was held at a temperature consisting of 60 ° C. to 70 ° C. for 1 hour and it was slowly cooled to 0 ° C. to hold it at this temperature for additional time. The resulting white precipitate was filtered and dried in vacuo for 14 hours to afford 31.08 g of product. And 1,200 ml of ethanol were mixed with 31.08 g of the obtained product and it was heated at 80 ° C. for 30 minutes, the volume of ethanol was concentrated in half by distillation, it was gradually cooled at room temperature and then at 0 ° C. for 1 hour Cooled. (R) -Tolterodine L-tartrate was obtained by filtration and vacuum dried at 60 ° C. for 14 hours to give 27.51 g of product. This method is repeated in the second case with 27.51 g of recrystallized (R) -tolterodine L-tartrate to produce a selectively activatable compound with a purity of 22.23 g of 99.80%.

By providing the process for preparing 3,3-diphenylpropylamine of the general formula (I) of the present invention [1] [2], 3,3-diphenyl is more effective than the prior art in terms of cost and productivity. Propilamine and pharmaceutical compositions thereof.

Claims (35)

As a manufacturing method (1) of 3, 3- diphenyl propylamine of general formula (I), its enantiomer, or its mixture, its solvent compound, hydrate, or salt;

here, R ₁ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or an alkoxyalkyl of the formula — (CH ₂ ) nOR ₅ wherein n is an integer of 1 to 3 and R ₅ is C ₁ -C ₆ alkyl And; R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO _2, CN, free or protected CHO, CH ₂ OH or R ₆ is H or C ₁ -C ₆ alkyl group, a COOR ₆ ; R ₃ and R ₄ are independently selected from H and C ₁ -C ₈ alkyl or they are selected together with nitrogen formed by bonding a ring having 3 to 7 components; The method, a) R ₃ and R ₄ are as described above

A compound of formula (II), R ₁ and R ₃ are as described above

A reaction step of; And b) if necessary, separating (R) or (S) enantiomers, or mixtures of enantiomers, and / or converting the compounds of formula (I) to their salts 3,3-diphenylpropylamine of (I), enantiomer thereof, or a mixture thereof, a method for producing a solvent compound, hydrate, or salt thereof. The method of claim 1, A process for preparing 3,3-diphenylpropylamine of formula (I) wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in a reaction medium consisting of an acid. The method of claim 2, A process for producing 3,3-diphenylpropylamine of the general formula (I), wherein the acid is an inorganic acid. The method of claim 3, wherein A process for producing 3,3-diphenylpropylamine of the general formula (I), wherein the inorganic acid is hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid, and mixtures thereof. The method of claim 2, A process for producing 3,3-diphenylpropylamine of the general formula (I), wherein the acid is an organic acid. The method of claim 5, wherein A process for producing 3,3-diphenylpropylamine of general formula (I), wherein the organic acid is selected from p-toluenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, and mixtures thereof. The method of claim 2, A process for preparing 3,3-diphenylpropylamine of general formula (I), wherein the reaction medium comprises one or more inorganic acids and one or more organic acids. The method of claim 7, wherein A process for preparing 3,3-diphenylpropylamine of formula (I) wherein the reaction medium comprises an organic acid such as acetic acid and an inorganic acid selected from hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid and mixtures thereof. The method of claim 2, A process for producing 3,3-diphenylpropylamine of the general formula (I), wherein the acid is a Lewis acid. The method of claim 9, A method for producing 3,3-diphenylpropylamine of the general formula (I), wherein the Lewis acid is AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF ₃ , or a mixture thereof. The method according to any one of claims 1 to 10, In the obtained compound of formula (I), 3,3 of formula (I) wherein R ₁ is H or methyl, R ₂ is methyl, and R ₃ and R ₄ are both isopropyl or salts thereof. A process for the preparation of diphenylpropylamine. The method according to any one of claims 1 to 10, The compound of formula (I) obtained is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine hydrobromide or The manufacturing method of 3, 3- diphenyl propylamine of general formula (I) which is a salt. The method of claim 12, The compound of general formula (I) obtained is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine hydrobromide or (R Of 3,3-diphenylpropylamine of the general formula (I) which is)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine tartrate Manufacturing method. 3,3-diphenylpropylamine of the general formula (I '). As a process for producing an enantiomer thereof or a mixture thereof, a solvent compound thereof, a hydrate or a salt thereof;

here, R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO ₂ , C _N , CHO, CH ₂ OH or COOR ₆ , which may be free or protected, wherein R ₆ is H or C _1- C ₆ alkyl; R ₃ and R ₄ are selected together with H, C ₁ -C ₈ alkyl, or nitrogen formed by bonding a ring having 3 to 7 components; This way, a) R ₃ and R ₄ are as defined above

A compound of formula (II),

Alkoxyalkyl of the formula-(CH ₂ ) nOR ₅ , wherein R ' ₁ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or n is an integer from 1 to 3, and R ₅ is C ₁ -C ₆ alkyl ego ; And, R ₂ is reacted with a compound of formula (III ′) as defined above;

R ' ₁ , R ₂ , R ₃ and R ₄ generate a compound of formula (I ″) as defined above; b) converting R ' ₁ to hydrogen to obtain a compound of formula (I'); And c) if desired, separating the intended (R) or (S) enantiomers, or mixtures of enantiomers, and / or converting the compounds of formula (I ′) to their salts. 3,3-diphenylpropylamine of the general formula (I '). Process for preparing enantiomers thereof or mixtures thereof, solvates, hydrates or salts thereof. The method of claim 14, A process for preparing 3,3-diphenylpropylamine of formula (I ') wherein the reaction of the compound of formula (II) with the compound of formula (III') is carried out in a reaction medium consisting of an acid. The method of claim 15, A method for producing 3,3-diphenylpropylamine of the general formula (I '), wherein the acid is an inorganic acid except hydrobromic acid. The method of claim 16, A process for producing 3,3-diphenylpropylamine of the general formula (I '), wherein the inorganic acid is selected from perchloric acid, sulfuric acid, and mixtures thereof. The method of claim 15, A method for producing 3,3-diphenylpropylamine of the general formula (I ') wherein the acid is an organic acid. The method of claim 18, A method for producing 3,3-diphenylpropylamine of the general formula (I '), wherein the organic acid is selected from p-toluenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid and mixtures thereof. The method of claim 15, A process for preparing 3,3-diphenylpropylamine of the general formula (I '), wherein the reaction medium is one or more inorganic acids and one or more organic acids except hydrobromic acid. The method of claim 20, A process for preparing 3,3-diphenylpropylamine of the general formula (I ') wherein the reaction medium comprises an inorganic acid selected from the group consisting of perchloric acid, sulfuric acid and mixtures thereof and organic acids such as acetic acid. The method of claim 15, A method for producing 3,3-diphenylpropylamine of the general formula (I ') wherein the acid is a Lewis acid. The method of claim 22, A method for producing 3,3-diphenylpropylamine of the general formula (I '), wherein the Lewis acid is AlCl ₃ , SnCl ₄ , ZnCl ₂ , BF ₃ , or a mixture thereof. The method according to any one of claims 14 to 23, A method for producing 3,3-diphenylpropylamine of the general formula (I ') wherein R ₂ is methyl and R ₃ and R ₄ are isopropyl or a salt thereof in the obtained compound of general formula (I'). The method according to any one of claims 14 to 23, The compound of formula (I ′) obtained is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or salts thereof Method for producing 3,3-diphenylpropylamine of the general formula (I '). The method of claim 25, The obtained compound of formula (I ') is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine hydrobromide or ( 3,3-diphenylpropyl of general formula (I ') which is R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine tartrate Amine Preparation Method. As a method for producing 3,3-diphenylpropylamine of the general formula (I), enantiomer thereof or mixture thereof, solvate, hydrate or salt thereof;

here, R ₁ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or alkoxyalkyl of the formula — (CH ₂ ) nOR ₅ wherein n is an integer from 1 to 3 and R ₅ is C ₁ -C ₆ alkyl ; R ₂ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, NO ₂ , CN, COOR wherein CHO, CH ₂ OH, R ₆ is free or protected, H or C ₁ -C ₆ alkyl group ₆ ; R ₃ and R ₄ are independently selected from H and C ₁ -C ₈ alkyl or are selected together with nitrogen which is formed by bonding a ring having 3 to 7 components; The method, a) Y is an exit group

(IV) A compound of formula (IV), R ₃ and R ₄ are independently selected from hydrogen and straight or branched C ₁ -C ₈ alkyl, or independently selected with nitrogen formed by combining a ring having 3 to 7 components of formula (V) The first or second amine reacts;

Obtaining a compound of formula (II);

b) R ₁ and R ₂ reacting said compound of formula (III) with said compound of formula (II) as described above; And,

c) if desired, separating the desired (R) or (S) enantiomer, or a mixture of enantiomers, and / or converting a compound of formula (I) to a salt thereof 3,3-diphenylpropylamine of the general formula (I), enantiomers thereof or mixtures thereof, solvates, hydrates, or salts thereof. The method of claim 27, In the general formula (I) obtained, 3,3-diphenylpropyl of general formula (I) wherein R ₁ is H or methyl, R ₂ is methyl and R ₃ and R ₄ are both isopropyl or salts thereof. Amine Preparation Method. The method of claim 27, General formula wherein the obtained compound of formula (I) is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or salts thereof 3,3-diphenylpropylamine production method of formula (I). The method of claim 27, The compound of general formula (I) obtained is (R)-(+)-N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine hydrobromide or (R 3,3-diphenylpropylamine of the general formula (I) which is)-(+)-N, N-diisopropylamine-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine tartrate Manufacturing method. Acid addition salt of the compound of general formula (II) which consists of a compound of general formula (11) and an acid. The method of claim 31, wherein Acid addition salts wherein the acid is an organic or inorganic acid. The method of claim 31 or 32, Addition salts which are hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate or maleate of general formula (II). The method according to any one of claims 31 to 33, wherein Addition salts wherein R ₃ and R ₄ are isopropyl. The method according to any one of claims 31 to 34, wherein Addition salts which are N, N-diisopropyl-3-phenyl-2-propeneamine hydrochloride and N, N-diisopropyl-3-phenyl-2-propeneamine hydrobromide.